Prostate cancer is one of the most common forms of cancer for males in the developed world. In spite of the significant occurrence of this condition, the treatments of those males who have prostate cancer are less than optimal. Current efforts are on early detection and treatment. While this seems to have the greatest effect on survival by males, the primary treatments after early detection and diagnosis typically are surgery, brachytherapy, or external beam radiation. If the carcinoma has not metastasized, generally no adjuvant treatment after the primary treatment is indicated and the patient is monitored for reoccurrence of the cancer. However, if the carcinoma has metastasized, the current treatment after the primary treatment is androgen ablation. The present treatments for metastasized prostate cancer may fail over time as many patients ultimately develop hormone refractory prostate carcinoma that is resistant to the effects of androgen ablation.
Typical androgen ablation therapies include surgical or chemical castration or the administration of a combination of an LHRH agonist and a nonsteroidal antiandrogen drug, such as flutamide, bicalutamide, and nilutamide. The combination therapy is necessary because there still is some level of testosterone in the blood stream after treatment with castration or with the LHRH agonists. This residual level of testosterone is thought to come from secondary sources in the body, such as the adrenal gland. The nonsteroidal antiandrogen drugs block the binding of testosterone and its metabolite dihydrotestosterone to the androgen receptor in the cancer cells and thereby inhibit cell proliferation.
The drugs used in the treatment of prostate cancer also have differing but significant side effects for the majority of males, including impotence, hot flashes, gynecomastia, breast tenderness, liver toxicity, osteoporosis, depression, heart disease, gastro-intestinal disorders, and loss of cognitive function. The primary side effects for the nonsteroidal antiandrogen drugs include gynecomastia, breast tenderness, and gastro-intestinal disorders. These side effects are often so significant that many patients stop treatment with these drugs with the increased risk of progression of the cancer. See European Urology 1996 :29 (suppl 2): 124-131. At present, the gynecomastia and breast tenderness are treated either after the fact, sometimes by surgery to remove tissue, or the patient is treated with radiation prior to beginning the drug therapy. U.S. Pat. No. 4,895,715 discloses a method of treating gynecomastia in patients being treated with an antiandrogen for androgen dependent conditions such as benign prostatic hypertrophy by administering the antiandrogen in association with an antiestrogen compound, such as tamoxifen.
There has also been a proposal to treat prostate cancer with an adjuvant monotherapy involving only the nonsteroidal antiandrogen drugs, typically at a relatively high dose, after the primary treatment. This trial has been inconclusive as to the effectiveness of the nonsteroidal antiandrogen drugs to slow the reoccurrence of prostate cancer. However, there have been studies that show that bicalutamide seems to have a role in cancer cell death.
It has also been known that prostate cancer cells have estrogen receptors. For this reason, Bergan, et al (Clinical Cancer Research, Volume 5, pages 2366-2373, September 1999) proposed the treatment of prostate cancer with high doses of tamoxifen, a selective estrogen receptor modulator (SERM). This study showed that high doses of tamoxifen alone have some effect on the prostate cancer cells for patients that have metastasized prostate cancer and also have hormone refractory prostate cancer.
Other SERM's, such as raloxifene and toremifene, also have been shown to have some effect on the progression of metastasized prostate cancer. In a manner similar to the tamoxifen study reference above, these SERM's have some effect on metastasized prostate cancer. Also, there have been studies that seem to show that SERM's have a role in prostate cancer cell death.
While there have been studies with low doses of nonsteroidal antiandrogen drugs and there is one current study with a high dose of nonsteroidal antiandrogen drugs, at the present time, for patients without metastasized prostate cancer, there is no adjuvant treatment as a follow on treatment after the primary treatment. One reason for this is the side effects as described above of the drugs used for treatment of prostate cancer and the concern that these drugs have minimal inhibitory effect on the progression of prostate cancer compared to the efficacy of the LHRH analogs.